It is known that certain mevalonate derivatives inhibit the biosynthesis of cholesterol, cf F. M. Singer et al, Proc. Soc. Exper. Biol. Med., 102, 270 (1959) and F. H. Hulcher, Arch. Biochem. Biophys., 146, 422 (1971). Nevertheless, the activity of these known compounds has not always been found to be satisfactory, i.e. to have practical application.
Recently, Endo et al, reported (U.S. Pat. No. 4,049,495, U.S. Pat. No. 4,137,322 and U.S. Pat. No. 3,983,140) the production of fermentation products which were quite active in the inhibition of cholesterol biosynthesis. The most active member of this group of natural products, now called compactin, was reported by Brown et al, J. Chem. Soc. Perkin I 1165 (1976) to have a complex mevalonolactone structure.
More recently Monaghan et al (U.S. Pat. No. 4,231,938) reported an even more potent inhibitor, III.sub.a having the structure ##STR3## isolated from an entirely different fermentation. Albers-Schonberg et al (U.S. Ser. No. 154,157, filed May 28, 1980) described a dihydro III.sub.a, designated III.sub.d in Flow Sheet B, of equal potency isolated from the same fermentation.
Patchett et al, (U.S. Ser. No. 118,050, filed Feb. 4, 1980, now abandoned) describe dihydro and tetrahydro derivatives of III.sub.a of different structures, prepared by the catalytic hydrogenation of III.sub.a, designated III.sub.b, III.sub.c and III.sub.e in Flow Sheet B.
The fermentation products reported by Endo included an .alpha.-methylbutyryl ester (ML236B) and the corresponding alcohol of the compactin ring system (ML236A). However, in the fermentation which produced III.sub.a and III.sub.d, the only products isolated were the methylbutyryl esters, no free alcohol corresponding to these esters being detected.
The preparation of the starting material, III.sub.d, as mentioned previously, is described by Albers-Schonberg et al in U.S. application, Ser. No. 154,157, filed May 28, 1980 and is a product of the following fermentation with a strain of Aspergillus terreus, ATCC No. 20542, designated MF-4845 in the culture collection of MERCK & CO., Inc. Rahway, N.J.